HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia.

Mursal Sherzai,Sahar Al-Mahdawi,Nicholas Perry,Sara Anjomani Virmouni,Mark Pook,Adamo Valle,Ester Kalef-Ezra

doi:10.3389/fgene.2020.00584

Abstract

Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disorder caused by a homozygous GAA repeat expansion mutation in intron 1 of the frataxin gene (FXN), which instigates reduced transcription. As a consequence, reduced levels of frataxin protein lead to mitochondrial iron accumulation, oxidative stress, and ultimately cell death; particularly in dorsal root ganglia (DRG) sensory neurons and the dentate nucleus of the cerebellum. In addition to neurological disability, FRDA is associated with cardiomyopathy, diabetes mellitus, and skeletal deformities. Currently there is no effective treatment for FRDA and patients die prematurely. Recent findings suggest that abnormal GAA expansion plays a role in histone modification, subjecting the FXN gene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, we investigated the efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increased FXN gene expression levels and reduced the repressive histone marks. However, no increase in frataxin protein levels was observed. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies.

Highlights

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia
It has been reported that 98% of FRDA patients have a homozygous GAA trinucleotide repeat expansion within the first intron of the FXN gene, leading to reduced expression of frataxin (Campuzano et al, 1996)
The mechanism by which the GAA repeat expansion leads to decreased levels of frataxin are currently unknown, it is generally accepted that FRDA may be caused by a heterochromatin-mediated silencing effect of the FXN gene (Saveliev et al, 2003; Festenstein, 2006)

Summary

Introduction

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia It is caused by homozygous GAA repeat expansion mutation within intron 1 of the frataxin (FXN) gene (Campuzano et al, 1996), which induces FXN gene silencing and reduced expression of the essential mitochondrial protein frataxin (Campuzano et al, 1997). There is currently no effective treatment for FRDA, advances in research of its pathogenesis have led to a wide range of therapeutic strategies that are being tested in clinical trials. These include the use of antioxidants such as idebenone, EPIA0001 and pioglitazone; iron chelators such as deferiprone; and frataxin-increasing compounds such as erythropoietin (EPO) and histone deacetylase (HDAC) inhibitors (Schulz et al, 2009). There is still a high unmet clinical need to develop effective FRDA therapies

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